Bottom Line:
Although the physiological role of AP-3A has recently been elucidated, that of AP-3B remains unsolved.This facilitated the induction of long-term potentiation in the hippocampus and the abnormal propagation of neuronal excitability via the temporoammonic pathway.Thus, AP-3B plays a critical role in the normal formation and function of a subset of synaptic vesicles.

ABSTRACTAP-3 is a member of the adaptor protein (AP) complex family that regulates the vesicular transport of cargo proteins in the secretory and endocytic pathways. There are two isoforms of AP-3: the ubiquitously expressed AP-3A and the neuron-specific AP-3B. Although the physiological role of AP-3A has recently been elucidated, that of AP-3B remains unsolved. To address this question, we generated mice lacking mu3B, a subunit of AP-3B. mu3B-/- mice suffered from spontaneous epileptic seizures. Morphological abnormalities were observed at synapses in these mice. Biochemical studies demonstrated the impairment of gamma-aminobutyric acid (GABA) release because of, at least in part, the reduction of vesicular GABA transporter in mu3B-/- mice. This facilitated the induction of long-term potentiation in the hippocampus and the abnormal propagation of neuronal excitability via the temporoammonic pathway. Thus, AP-3B plays a critical role in the normal formation and function of a subset of synaptic vesicles. This work adds a new aspect to the pathogenesis of epilepsy.

Mentions:
The frequency of birth of μ3B−/−ΔNeo mice was in accordance with Mendelian expectations. The mice were fertile and survived for at least more than one year. Although the μ3B−/−ΔNeo mice appeared normal, some adult mice exhibited spontaneous epileptic seizures upon presentation of such stimuli as positional change (Video 1, available at http://www.jcb.org/cgi/content/full/jcb.200405032/DC1). More than half of the mice suffered from seizures at the age of 15 wk or over. In addition, the electrocorticogram revealed that all of the μ3B−/−ΔNeo mice tested showed an abnormal epileptic pattern, namely, interictal spikes, which was never observed in wild-type mice (Fig. 2 A). These observations prompted us to test the seizure susceptibility of μ3B−/−ΔNeo mice.

Mentions:
The frequency of birth of μ3B−/−ΔNeo mice was in accordance with Mendelian expectations. The mice were fertile and survived for at least more than one year. Although the μ3B−/−ΔNeo mice appeared normal, some adult mice exhibited spontaneous epileptic seizures upon presentation of such stimuli as positional change (Video 1, available at http://www.jcb.org/cgi/content/full/jcb.200405032/DC1). More than half of the mice suffered from seizures at the age of 15 wk or over. In addition, the electrocorticogram revealed that all of the μ3B−/−ΔNeo mice tested showed an abnormal epileptic pattern, namely, interictal spikes, which was never observed in wild-type mice (Fig. 2 A). These observations prompted us to test the seizure susceptibility of μ3B−/−ΔNeo mice.

Bottom Line:
Although the physiological role of AP-3A has recently been elucidated, that of AP-3B remains unsolved.This facilitated the induction of long-term potentiation in the hippocampus and the abnormal propagation of neuronal excitability via the temporoammonic pathway.Thus, AP-3B plays a critical role in the normal formation and function of a subset of synaptic vesicles.

ABSTRACTAP-3 is a member of the adaptor protein (AP) complex family that regulates the vesicular transport of cargo proteins in the secretory and endocytic pathways. There are two isoforms of AP-3: the ubiquitously expressed AP-3A and the neuron-specific AP-3B. Although the physiological role of AP-3A has recently been elucidated, that of AP-3B remains unsolved. To address this question, we generated mice lacking mu3B, a subunit of AP-3B. mu3B-/- mice suffered from spontaneous epileptic seizures. Morphological abnormalities were observed at synapses in these mice. Biochemical studies demonstrated the impairment of gamma-aminobutyric acid (GABA) release because of, at least in part, the reduction of vesicular GABA transporter in mu3B-/- mice. This facilitated the induction of long-term potentiation in the hippocampus and the abnormal propagation of neuronal excitability via the temporoammonic pathway. Thus, AP-3B plays a critical role in the normal formation and function of a subset of synaptic vesicles. This work adds a new aspect to the pathogenesis of epilepsy.